The iris sphincter of eyes which are treated chronically with various cholinesterase inhibitors become subsensitive to the antiChE agent itself and to cholinomimetics. Such antiChE induced subsensitivity does not develop in chronically parasympathetically denervated (supersensitive) eyes unless exogenous ACh is supplied by repeated intravitreal injections. The purpose of the proposed experiments is to further elucidate the nature of the control of the neurotransmitter and drug sensitivity of intraocular tissues which are normally under the influence of the autonomic system and to relate these findings more directly to the diagnosis, etiology and treatment of glaucoma. We shall conduct studies on the sensitivity-control of cholinergic functions which are directly involved in the control of intraocular pressure. The effect of various experimental conditions which were shown to alter the cholinergic sensitivity of the iris sphincter will be tested for the pilocarpine and carbachol sensitivity of outflow resistance. Development of insensitivity to the ocular hypotensive effects of cholinomimetics in the rhesus monkey will be studied in relation to the general problems of experimentally induced subsensitivity and development of insensitivity to clinically used drugs. The specificity of experimentally induced super-and subsensitivity will be investigated on the isolated rat eye using miosis as a criteria. Interaction between various autonomic drugs will be studied both in vivo and in vitro at different levels of sensitivity.